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Enzyme Promiscuity: Using the Dark Side of Enzyme Specificity in White Biotechnology Benu Arora1, Joyeeta Mukherjee1 and Munishwar Nath Gupta2*

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Enzyme Promiscuity: Using the Dark Side of Enzyme Specificity in White Biotechnology Benu Arora1, Joyeeta Mukherjee1 and Munishwar Nath Gupta2* Arora et al. Sustainable Chemical Processes (2014) 2:25 DOI 10.1186/s40508-014-0025-y REVIEW Open Access Enzyme promiscuity: using the dark side of enzyme specificity in white biotechnology Benu Arora1, Joyeeta Mukherjee1 and Munishwar Nath Gupta2* Abstract Enzyme promiscuity can be classified into substrate promiscuity, condition promiscuity and catalytic promiscuity. Enzyme promiscuity results in far larger ranges of organic compounds which can be obtained by biocatalysis. While early examples mostly involved use of lipases, more recent literature shows that catalytic promiscuity occurs more widely and many other classes of enzymes can be used to obtain diverse kinds of molecules. This is of immense relevance in the context of white biotechnology as enzyme catalysed reactions use greener conditions. Keywords: Enzyme specificity, Catalytic promiscuity, Enzymes in organic synthesis, Enantioselectivity, Green chemistry is concerned. The most dramatic departure from the “I suspect they put Socrates to death because there is classical concept of enzyme specificity is seen in the something terribly unattractive, alienating and non- phenomenon of catalytic promiscuity. This refers to human in thinking with too much clarity.”- the same enzyme catalyzing very different kinds of bio- transformations [3-6]. The Bed of Procrustes by Nassim Nicholas Taleb Classification of enzymes and enzyme specificity Introduction Most of the people have forgotten (understandable since it The basic tenet of white biotechnology is to minimize disappeared from the standard texts many decades back!) damage to the environment rather than taking recourse that initially proteins were classified according to their to remediation as an “end of the pipe” solution [1,2]. En- solubility in various solvents. The five classes of proteins zymes either in isolated form or in the form of whole cells were albumins (soluble in water and salt solutions), globu- can play an important role because of their two well lins (sparingly soluble in water but soluble in salt solu- known virtues. The biocatalysts normally do not require tions), prolamines (soluble in 70-80% ethanol), glutenins high temperature or other conditions which involve high (soluble in acid or alkali) and scleroproteins (insoluble in consumption of energy. The biocatalysts are believed to aqueous solvents) [7]. As our knowledge of proteins grew, be fairly specific, which would mean less number of side the distinction between these various classes became fluid reactions. Side reactions lead to side products which lower and in fact confusing. The enzymes, in the early phase the atom economy of the reactions. These side reactions of biochemistry became the most important and most hence lower the yield of the desired product (making the studied class of proteins. These were named in a random catalysis less efficient) and necessitate complicated down- fashion just as people name buildings, streets and monu- stream processing. ments. Many of these names persist e.g. catalase, trypsin, This review discusses the paradigm shifts over the years lysozyme etc. Many of these names were based upon the in our understanding of the enzyme specificity. It also ex- nature of their catalytic activity. Lysozyme is named so as plains why so called lack of specificity is also a good news it lyses cells. So, the nomenclature and catalytic specificity as far as the usefulness of enzymes in biotechnology have a long history in the area of biocatalysis. The idea of a particular structure being absolutely related * Correspondence: [email protected] to a biological activity has been considered the hallmark of 2Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India biology for many decades. Hence, it is not surprising that Full list of author information is available at the end of the article enzyme commission classification was based upon the type © 2014 Arora et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Arora et al. Sustainable Chemical Processes (2014) 2:25 Page 2 of 9 of reaction the enzyme catalyzes –hydrolysis, isomerisation “alternative substrates”, hydrophobic interactions may or redox reactions etc. [8]. This in retrospect may not have have an important role to play. Not only during binding, been such a wise move as we believed till now. even during catalytic steps, the contributions of the ac- In 1955–56, International Commission of enzymes was tive site residues may differ qualitatively and/or quanti- set up and that is how the EC classification came into be- tatively. This “accidental promiscuity” observed in wild ing [8]. As we know, this classification provides a number forms of the enzymes should be distinguished from “in- with four figures. It is worth noting that all the four figures duced promiscuity” exhibited by mutants obtained by relate to the details of the specificity of the enzyme. The protein engineering or directed evolution [12]. Many ex- firm belief was that if one is able to pin down complete cellent reviews (other than those already quoted above) details of the specificity, one has described the enzyme which include evolutionary aspects of promiscuity are and that is its identity. available [3,13,14]. Various kinds of enzyme promiscuity Condition promiscuity of enzymes Nothing promotes a scientific direction asmuch as coining Hydrolases hydrolyse substrates. What happens if water a new term. System biology, nanotechnology and synthetic is nearly absent? Advent of non-aqueous enzymology biology are illustrative examples. Enzyme promiscuity is showed that exploring this possibility led to carrying out also a case in point. As Hult and Burglund [9] pointed biocatalysis in nearly anhydrous organic solvents [15,16], out, promiscuous catalysis by pyruvate decarboxylase of reverse micelles [17,18], ionic liquids [19-22] etc. So, a formation of C-C bonds was reported in 1921 and forms lipase in low water containing organic solvent synthe- the basis of a current industrial process. Khersonsky and sizes an ester bond and is obviously not functioning as a Tawfik [4] have also cited examples of few other well hydrolase [23]. known enzymes which, many decades back, were reported This has been a very useful discovery. It has been also to catalyse reactions “in addition to the ones for which very important as it opened up huge possibilities of they are physiologically specialized or evolve…”. As Babtie using enzymes in biotransformations [16,24] [Figure 1]. et al. [10] highlighted “Promiscuous activities are generally Not only it makes it possible to use inexpensive hydrolases considerably less efficient than the primary function of an like proteases and lipases in organic synthesis, it provides enzyme, but second order rate constants (kcat/KM)ashigh an additional handle of medium engineering [25,26]. Chan- 5 −1 −1 as 10 M s and rate accelerations ((kcat/KM)/k2)upto ging the organic solvent may change the enantioselectivity 1018 have been reported: these values match or exceed [27,28]. The other possibilities emerged e.g. using organic those for many native enzymatic reactions.”. After initial solvents as co-solvents [29] or using biphasic systems con- loose usages of the terms (associated with promiscuous sisting of aqueous medium and water immiscible organic behaviour of enzymes), there is clarity that broad specifi- solvents [30]. One can use organic solvent phase to dis- city of an enzyme in terms of catalysis of the same reac- solve substrates and aqueous phase can contain the en- tion with range of substrates should be called substrate zyme. This makes the catalytic process very efficient in promiscuity. Instances when an enzyme catalyses a differ- case the substrate inhibition is involved [31]. If the prod- ent reaction (which is not believed to be physiologically uct also goes back to the organic phase, shifting of the relevant at that point in evolution) with a different transi- equilibrium (in favour of product formation) and over- tion state should be termed as examples of catalytic prom- coming product inhibition (if involved) are both achieved. iscuity [9,10]. More new possibilities continue to emerge. As Dordick’s Hult and Berglund [9] go a step further and suggest that group showed few years back, nanotube mediated assem- reverse reactions catalysed by enzymes in many non- bly of enzymes at the interface of aqueous and organic aqueous media or co-solvents can be classified as condition media overcomes the transport limitations typical of such promiscuity. In such cases, the transition state may be same biphasic systems [32]. as in normal reactions. So, this may be little confusing. It incidentally also meant that one could use green sol- Enzyme promiscuity started as being perceived as “asso- vents for biocatalysis such as glycerol, ethanol, succinate ciated with unwanted side effects, poor catalytic properties esters, lactate esters, limonene and supercritical fluids anderrorsinbiologicalfunction” [11]. Today, it is increas- [34]. The case of glycerol is especially relevant in the con-
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